The significance of hepatic stellate cell activation on small-for-size fatty liver graft injury

Abstract

BACKGROUND AND OBJECTIVE: The impact of hepatic stellate cell activation on liver graft injury at early phase after liver transplantation using marginal liver grafts have not been well studied. In the current study, we aim to investigate the significance of hepatic stellate cell activation in small-for-size liver graft injury and the underlying precise molecular mechanisms in a rat liver transplantation model using fatty grafts and cirrhotic recipients. MATERIALS AND METHODS: Male SD rats were used to establish the animal models. Fatty liver was induced by higher-fat diet. Cirrhotic liver was induced by subcutaneous injection of 50% carbon tetrachloride. A rat model of non-arterialized orthotopic liver transplantation without veno-venous by-pass using fatty liver grafts (40% of fatty changes) and cirrhotic recipients will be used. Lobe ligation technique was used to reduce the graft size on the back table. The median ratio of the graft weight to the recipient liver weight (graft weight ratio) was around 60%. Liver tissues and blood were sampled at 2, 4, 7, and 14 days after reperfusion for detection of hepatic stellate cell activation, intragraft gene expression, morphological examination including electron microscopy, and liver function tests. RESULTS: Significant activation of hepatic stellate cells was mainly found in small-for-size fatty grafts during the first 2 weeks after liver transplantation. The activation of HSCs was well correlated with progressive hepatic sinusoidal damage, together with the poor liver function. Gene expression profiles of the cell signaling pathways leading to acute phase inflammatory responses and angiogenesis were more over-expressed in small-for-size fatty grafts than those of whole grafts at different time points detected by real-time RT PCR. Hepatic ultrastructure of small-for size fatty liver graft was demonstrated with sinusoidal disruption, cytoplasm degeneration and mitochondrial swelling in hepatocytes, and collapse of Disse space with electron microscopy. CONCLUSIONS: Significant activation of hepatic stellate cell plays important roles in small-for-size fatty liver graft injury. The findings of this study on hepatic stellate cell activation may lay the foundation for the prophylactic treatment for patients with severe cirrhosis using fatty liver grafts.